Over the last three years, our laboratory has been systematically defining pathogenetic mechanisms that are operative in the autoimmune cutaneous disease pemphigus. The animal model we had developed, employing passive transfer of human autoantibodies in neonatal mice, has allowed us to define these mechanisms in vivo. It is our intention to extend these studies to define the role of plasminogen activator in the production of lesions in vivo, to examine the potential importance of other proteinases by using proteinase inhibitors of various specificities to inhibit acantholysis, and to examine the possible therapeutic effect of drugs that interfere with cell surface-cytoskeleton interactions and internalization. A longterm goal is to expand the current model and attempt to produce disease in these animals by immunization with antigen. This would allow us to examine many more aspects of this complex autoimmune disease such as immune regulation by idiotypic and anti-idiotypic networks. Bullous pemphigoid (BP) is another cutaneous blistering disease in which autoantibodies are present. We have recently shown that antibodies from BP patients bind specifically in the area of the cytoplasmic attachment plaque of the epidermal basal cell hemidesmosome. We propose a series of studies to define if there are distinct populations of autoantibodies that bind to intracellular and/or extracellular BP antigens, if the different populations of antibodies are complement fixing, and if extracellular antigen is present in skin only from certain areas of the body. Once these questions are answered, we will examine the pathogenicity of these defined autoantibodies in vivo in mice and in the rabbit cornea. It is also possible that factors that permeabilize the basel cell membrane such as trauma and UV light are necessary to initiate cutaneous lesions, and these autoantibodies can then bind the cytoplasmic antigen, activate complement and propagate the lesion. This series of studies will help us understand the pathophysiology of this complex blistering disease in vivo.